Protease-activated receptor-2 (PAR2) is expressed in various cells in the airways and lungs. Increasing evidence has suggested that activation of PAR2 contributes to airway inflammation and airway hyperresponsiveness, the prominent features of many respiratory diseases including asthma. The mechanism underlying the potent actions of PAR2 in the airways and lungs remains to be elucidated;and an involvement of neurogenic mechanisms caused by the activation of bronchopulmonary sensory nerves, particularly C-fiber afferents has been recently suggested. The long-range goal of this research project is to elucidate the mechanism that how the interaction between PAR2 and bronchopulmonary C-fibers is involved in the pathogenesis of asthma. Airway acidification occurs in asthmatic patients, and affects airway functions by numerous pathways. One prominent consequence of acidification in the airways is the stimulation of bronchopulmonary C- fibers. The primary objective of this R03 pilot proposal is to investigate the effect of PAR2 activation on the acid stress-induced bronchopulmonary C-fiber responses. Our hypothesis is that when PAR2 is activated by endogenous (e.g., mast cell tryptase and trypsin-like proteases) or exogenous (e.g., airborne allergens) agonists, the airway acidification-induced changes in airway functions may be amplified and collectively contributes to the disease process of asthma. Two specific aims have been proposed: 1) to determine the effect of PAR2 activation on vagal bronchopulmonary C-fiber responses to acid stress and to investigate the underlying cellular mechanisms;and 2) to determine the involvement of bronchopulmonary C-fibers in the PAR2 activation-induced airway hyperresponsiveness to acid stress, and to differentiate the relative contributions of cholinergic reflex and tachykininergic mechanisms. The in-vivo respiratory recording and in-vitro whole-cell patch-clamping will be carried out in the proposed studies. The results obtained from this proposal should improve our understanding of the pathogenic role of the interaction between PAR2 and bronchopulmonary sensory nerves, and offer novel therapeutic strategies for the treatment of airway inflammatory diseases such as asthma. PUBLIC HEALTH RELEVANCE: A decrease in airway luminal pH occurs in asthmatic patients, and has diverse effect on airway functions. A receptor called protease-activated receptor-2 is known to play an important role in the pathogenesis of asthma. The proposed project will investigate how activation of this receptor regulates the pulmonary sensory nerve responses to low pH in the airways, and how these interactions will affect the disease process of asthma.